Summary of work: The aim of this project is to assess the effects of aging at a behaviorallevel of analysis, to identify neurobiological mechanisms associated with these effects, and toevaluate interventions that might alter age-related performance decrements. Rodent models are tested in a battery of sensorimotor and learning/memory tasks. Neurochemical andneurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include dietary restriction, various pharmacologic treatments, and gene transfer via adenoviral vectors. Multiple genotypes are examined to determine possible genetic involvement in the pattern of age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rats using manipulations of the cholinergic and glutamatergic neurotransmitter systems of great current interest is the improved learning of aged rats treated with a combination of drugs stimulating glycine and polyamine receptors. In addition, specific inhibitors of butylcholinesterase also appear to have cognitive enhancing effects. Use of nitric oxide generating compounds has also proven to be a successful strategy for cognitive enhancement in aged rats. We have applied neuromorphological analysis using unbiased stereology to count neurons, synapses, microglia and astrocytes in hippocampi of mice of different ages. Results indicate no significant age-related changes; thus, age-related memory impairments do not seem to be related to morphological changes but rather to changes in neurotransmission likely involving the cholinergic and glutamatergic systems. Regarding impaired motor performance, we have now examined a knock-out mouse that has no D2 dopamine receptors (D2R) and noted selective deficits in motor behavior. We are planning to use this a model for further development of an adenoviral vector for gene transfer of this receptor which is reduced with advancing age in a number of species. In addition to motor performance, we have now demonstrated the involvement of D2R in hippocampal release of acetylcholine and maze learning. This observation provides an additional model to examine the therapeutic effects of gene transfer of the D2R receptor. - Aging, Brain, Glutamate, Acetylcholine, Dopamine, Gene Therapy, Stereology, Hippocampus, Memory, Alzheimer's disease